This Project focuses on the defining molecules that are necessary for phagocytosis. Phagocytosis is primary a specialized function of myeloid cells. Phagocytosis of microorganisms plays a key role in host defense. Engulfment of microorganisms and senescent cells by phagocytic cells is a complex multistep process. Hitherto, identification of molecules that play a key role in phagocytosis has been largely confined to in vitro mammalian systems. In this project, we propose to combine the powerful tools of Drosophila genetics that will allow us to study phagocytosis in vivo with in vitro cellular and biochemical studies that make use of Drosophila macrophage cell lines. Furthermore, we aim to apply the lessons learnt in Drosophila to mammalian systems. We plan to use both loss-of-function mutant analysis, and misexpression in vivo to explore the role of candidate molecules in this process. In addition, we propose three major genetic screens to detect other molecules that play a role in phagocytosis. We believe that the approaches outlined in this Project 1 of the Program Project Grant will provide new insights into the regulation of phagocytosis and, as such, will have direct applicability to gaining greater insights into microbial host interactions.